This project focuses on a mechanistic analysis of the transmembrane leucine-rich repeat protein Lrig1. Lrig proteins have recently emerged as novel modulators of membrane receptors with relevancy to mammary gland biology and tumorigenesis, including members of the ErbB pathway. The central hypothesis of this proposal is that Lrig1 plays a critical role in the post-transcriptional regulation of oncogenic receptors ad that perturbation of Lrig1 in breast cancer contributes to aberrant receptor expression, impacting tumor initiation and /or progression. In this proposal, we will focus our efforts on two independent aims which will expand our knowledge of the function of the Lrig1 in mammary gland biology and tumorigenesis. In Aim 1, we will exploit the Lrig1 knockout mice to define the role of Lrig1 in mammary gland development and oncogene-driven tumor development. In Aim 2, we will examine the role of Lrig1 in crosstalk between the estrogen receptor-a and ErbB2 with implications for endocrine resistance. PUBLIC HEALTH RELEVANCE: The proposed research will examine the role of the transmembrane leucine-rich repeat protein Lrig1 in mammary gland development and carcinogenesis. Lrig1 has recently emerged as a key post-transcriptional regulator of oncogenic receptors including ErbB2. Relatively little is known about the post-transcriptional regulation of receptor expression. Filling these knowledge gaps may expose opportunities which can be exploited to improve breast cancer treatment.